Download A need to simplify informed consent documents

Annals of Oncology 28: 922–930, 2017
doi:10.1093/annonc/mdx050
Published online 13 February 2017
SPECIAL ARTICLE
A need to simplify informed consent documents in
cancer clinical trials. A position paper of the ARCAD
Group
H. Bleiberg1*, G. Decoster2, A. de Gramont3, P. Rougier4, A. Sobrero5, A. Benson6, B. Chibaudel3,
J. Y. Douillard7, C. Eng8, C. Fuchs9, M. Fujii10, R. Labianca11, A. K. Larsen12, E. Mitchell13, H. J. Schmoll14,
D. Sprumont15 & J. Zalcberg16
1
Institut Jules Bordet, Brussels, Belgium; 2Freelance Auditor, Basel, Switzerland; 3Department of Medical Oncology, Institut Hospitalier Franco-Britannique, Levallois
Perret; 4Gastroenterology and Digestive Oncology Department, European Hospital, Georges Pompidou, Paris, France; 5Medical Oncology Unit, Ospedale San
Martino, Genova, Italy; 6Division of Hematology/Oncology, Robert H. Comprehensive Cancer Center Northwestern University, Chicago, USA; 7Department of
Medical Oncology, Centre R. Gauducheau Université de Nantes, Saint Herblain, France; 8Division of Cancer Medicine, Department of Gastrointestinal Medical
Oncology, The University of Texas MD Anderson Cancer Center, Houston; 9Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical
School, Boston, USA; 10Department of Digestive Surgery, Nihon University School of Medicine, Tokyo, Japan; 11Cancer Center, Ospedale Giovanni XXIII, Bergamo,
Italy; 12Laboratory of Cancer Biology and Therapeutics, INSERM and Université Pierre et Marie Curie, Saint-Antoine Hospital, Paris, France; 13Kimmel Cancer Center
at Jefferson, Jefferson University Hospitals, Philadelphia, USA; 14Department of Internal Medicine IV, University Clinic Halle, Martin-Luther-University HalleWittenberg, Halle, Germany; 15Institute of Health Law, University of Neuch^atel, Neuch^atel, Switzerland; 16Faculty of Medicine, Nursing and Health Sciences,
Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia
*Correspondence to: Prof. Harry Bleiberg, Montagne de Saint Job 109, Brussels, Belgium. Tel: þ32-23-75-27-02; E-mail: [email protected]
Background: In respect of the principle of autonomy and the right of self-determination, obtaining an informed consent of
potential participants before their inclusion in a study is a fundamental ethical obligation. The variations in national laws, regulations, and cultures contribute to complex informed consent documents for patients participating in clinical trials. Currently,
only few ethics committees seem willing to address the complexity and the length of these documents and to request investigators and sponsors to revise them in a way to make them understandable for potential participants. The purpose of this work
is to focus on the written information in the informed consent documentation for drug development clinical trials and suggests (i) to distinguish between necessary and not essential information, (ii) to define the optimal format allowing the best legibility of those documents.
Methods: The Aide et Recherche en Cancérologie Digestive (ARCAD) Group, an international scientific committee involving
oncologists from all over the world, addressed these issues and developed and uniformly accepted a simplified informed
consent documentation for future clinical research.
Results: A simplified form of informed consent with the leading part of 1200–1800 words containing all of the key information
necessary to meet ethical and regulatory requirements and ‘relevant supportive information appendix’ of 2000–3000 words is
provided.
Conclusions: This position paper, on the basis of the ARCAD Group experts discussions, proposes our informed consent
model and the rationale for its content.
Key words: inform consent, oncology, clinical trial, good clinical practice, ethics, Institution Review Board
Background
In respect of the principle of autonomy and the right of selfdetermination, obtaining an informed consent of potential
participants before their inclusion in a study is a fundamental
ethical obligation first stated in the Code of Nuremberg (1949)
[1] and later rooted in the Declaration of Helsinki (1964, last
C The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
V
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Special article
Annals of Oncology
revised 2013) [2]. Obtaining the informed consent of the patients
is thus mandatory before starting any investigational treatment.
The informed consent refers to a process of patient–physician
dialog followed by a written documentation that summarizes key
points. Despite the acceptance and implementation of international Good Clinical Practice standards (ICH-GCP E6) [3], the
variations in national laws, regulations and cultures contribute to
complex informed consent documents for patients participating
in clinical trials. Currently, only few ethics committees seem willing to address the complexity and the length of these documents
and to request investigators and sponsors to revise them in a way
to make them understandable for potential participants. It is urgent to provide an adequate, understandable and non-technical
informed consent documentation that respects the participants’
right to self-determination and thus better protects their treating
physicians and others involved in clinical research.
The Aide et Recherche en Cancérologie Digestive (ARCAD)
Group [4–6], an international scientific committee involving oncologists from Australia, Europe, Japan, Latin America and the
United States, is concerned by the complexity and poor readability of the written information presented in many informed consent documents. Such issues can discourage patients from
participating in a clinical trial or can prompt them to take a treatment that they would not have taken if they had more comprehensible information.
The purpose of this work is to focus on the written information
in the informed consent documentation for drug development
clinical trials and suggests (i) to distinguish between the information necessary for the patient to make an informed decision and
the information that, although important, are not essential to the
decision making process and (ii) to define the optimal format
allowing the best legibility of those documents. In the interests of
efficiency a simplified informed consent documentation also
needs to comply with the requirements of the ICH-GCP E6, the
Food and Drug Administration (FDA) 21 Code of Federal
Regulations section 50.25 (21 CFR 50.25) [7], the recent National
Cancer Institute (NCI) template [8] or any other local mandatory
requirements.
Why are these documents so difficult to
read and understand?
It is generally recognized that informed consent documents are
too long, too complex and poorly developed, with numerous abbreviations, redundancies, contradictions, unjustified recommendations and unnecessary medical details that patients do not
need to make an informed decision.
An important section of the informed consent document,
which remains difficult to tackle, is the information on survival
[9] and the treatment-inducing adverse reactions, their occurrence, duration and severity. The reasons for this propensity
must have multiple causes. The most important being the desire
to inform completely to the point that non-expert patients and/
or those with reading disabilities or poor understandings of
medico-technical issues are completely lost. Too much and too
detailed information might be seen as distracting from informed
choice [10]. One can hope that the new NCI template, made available in June 2013, will prove simpler. A randomized evaluation of
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its effectiveness is underway. Many less useful information can
make the informed consent document gratuitously lengthy, e.g. a
lack of reference to the content of a package insert for drugs that
have received a marketing authorization, the description risks of
standard testing, biopsies and other procedures which are
required in the protocol and that many patients already know
and would have otherwise consented, and to substantial rereviews and modification by local Institutional Review Boards
(IRBs) or Research Ethics Committees (RECs) [11].
ARCAD fully agrees with the recommendations made by several guidelines on the informed consent documents currently in
place [3, 12–16]. Using the NCI template [8], in compliance with
the recommendations found in FDA 21-CFR 50.25 and ICHGCP E6, ARCAD would like to improve the format and presentation of the content in those documents to ensure that the information is clear and can be understood and integrated.
The elements of the informed consent documents are dependent upon the stage of the disease under study, the complexity
of the trial design, as well as the product to be tested and its stage
of development. ICH-GCP E6 section 4.8.10 proposes 20 points
of the informed consent that should be covered in some detail
[3]. These 20 points are further taken up in FDA 21-CFR50.25 as
well as in the NCI template [8]. This should ensure that patients
receive the adequate information before their participation in a
clinical research and can make an informed decision.
We propose that the informed consent documentation be divided into sections, but all sections are part of a single document.
The first section should contain the leading information essentially based on the ICH-GCP E6 20 points; the second section can
contain the supportive and detailed elements (including information required by local regulation, IRBs, RECs or investigators).
An appendix section may contain more general information such
as a glossary explaining simple terms, standard treatment or complex treatment concepts (e.g. placebo, cross-over, pharmaco-genetic/genomic research, if necessary legal aspects). For those who
wish and receive approval from their IRBs or RECs, the leading
information section, alone, should allow the patient to make his
own decision.
Every word should be weighed as it is in the protocol and as it
will be in the final article. Its length must be predefined and
imposed as required when submitting an article or abstract. This
endeavor of simplicity and clarity is required throughout the entire document, text must be legible and easy-to-read that corresponds to an ‘eighth grade’ reading level according US standards
or Flesch Reading Ease grade level of 60–70 provided by most
word processing programs, a font of minimum 12 pc, be adequately paginated, bear a version number and the date of issue
(http://www.nlm.nih.gov/medlineplus/etr.html). The same effort
should be made assuring that the information is understandable
for research participants in any language. Verbatim translation
should be avoided as far as local and national particularities and
requirements need to be taken into consideration.
Leading information
The leading information section should contain around 1200–
1800 words (3–5 pages) and should enable a patient to make an
informed decision. The content must describe the study name
and background including the reason(s) for its conducting, a
doi:10.1093/annonc/mdx050 | 923
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brief description of the investigational treatment and the possible
treatment alternatives. In addition, the duration of participation
and the frequency of the visits with a summary of the examinations to be carried out that are not included in the routine practice must be included, the potential benefits and risks that the
patients may encounter as well as a summary of the clinically significant known adverse reactions expected during treatment. Less
significant adverse reactions can be placed in the additional information section. Everything that is related to the risk can obviously not be described, especially as the risks at the initiation of a
trial, are not well known. The philosophy is to share the risks as
we know them, explain that some events may lead to hospitalization and treatment of indefinite duration and that in rare occasions can cause death.
According to the NCI template, there is no standard definition
of adverse events frequency in the United States. In Europe, the
European guidelines for the summary of product characteristics
(SmPC) (September 2009) require that the frequency of adverse
events follows their requirements. In Table 1 you should use what
is required in your country, but the frequency rate must be given.
NCI template. Common (>20% and up to 100% of patients
receiving the drug/agent); occasional (between 4% and 20% of
patients), rare and serious (in <3% of patients), serious (is defined
as side-effects that may require hospitalization or may be irreversible, long-term, or life-threatening).
EU commission guideline on the SmPC September 2009. Very
common (1/10), common (1/100 to <1/10), uncommon
(1/1000 to <1/100), rare (1/10 000 to <1/1000), very rare
(<1/10 000).
The consent form must state that out of respect for the patient’s privacy, the confidentiality of their personal health information will not be disclosed by their healthcare providers
without their authorization, that they will be informed in a timely
manner of any relevant issue that may change their decision to
participate, and that potential injury will be treated and covered
by an insurance or other acceptable means to be specified. The
patient should also obtain the name of a contact person. Further
information on the rights of patient must be included in the ‘detailed information’ section.
Table 1 provides a sample of the leading information of the
consent form.
Relevant supportive information
Additional information is available to complement the leading
information, especially those concerning the conduct of the
study, the patients’ rights as well as the protections that the sponsor and the investigator will provide during and after their participation (monitoring and treatment of serious adverse
reactions, insurance for study-related inducing damages,. . .).
Ideally, the detailed information section should be around
2000–3000 words. The text should not contain abbreviations, in
particular those used for regulatory purposes (e.g. FDA, EMA,
SAE, GCP, REC, IRB etc.) which is of little concern to the patient.
Redundancies should be banned and therefore the content of
the information already provided in the leading information
sheet should not be repeated in the detailed information section
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Annals of Oncology
unless it is supportive to any demands that are not involved in
the decision-making. There is often not enough medical information on the effects of a new treatment on the unborn child;
this means that sexually active patients (both woman and man)
are required to use adequate methods of birth control during
study treatment.
According to ICH-GCP E6, the investigational product(s)
should be supplied by the sponsor and be provided to clinical
trial patients free of charge. In many countries, it is legally acceptable that routine medical practice laboratory tests and medical imaging examinations are covered by the patients’ health
insurance. In Europe, many national laws require that a procedure be in place for the reimbursement for expenses such as travel
and lodging for patients participating in clinical trials, or treatments for trial-related serious adverse reactions. Several national laws require that trial-related injuries be covered by a
clinical trial insurance taken by the sponsor before the trial
starts and be valid in the country where the trial is carried out.
Regardless of the legislation, article 22 of the Declaration of
Helsinki requires that a compensation scheme be in place in
case of trial-related injuries. Potential participants should be informed about this. Such requirement can also be derived from
general rules in liability laws.
Patients participating in clinical trials have the responsibility,
as a clinical research partner, to provide correct and complete information about their health history, cooperate with their caregivers, and comply with the protocol by keeping all clinic
appointments or canceling and rescheduling their visits.
Withdrawal is permitted at all times, with no impact on further
standard of care for their medical condition. Once a patient withdraws his consent, the withdrawal will prevent any further collection of information and data.
Table 2 provides relevant supportive information. Additional
annexes can be added to the informed consent documents, as
needed (Table A1).
Discussion
Legislation on informed consent has its origin in medical malpractices identified in the last century which were implemented
without consideration for the people and without any ethical
content [1, 17].
The content of informed consent documents stating what is
required to properly inform the patient participation in drug
trials has been agreed upon between various regulatory bodies
within the ICH region [3, 11–13], as well as in those countries
applying ICH standards. We did not expand here on the history
that led to the recommendations currently in place or refer to
the research carried out in this area. A recent review by
Christine [18] addresses these issues in terms of emerging challenges of informed consent when changing models of health
care and research, such as what information should be disclosed,
how it should be disclosed, how much the persons providing consent
should understand and how explicit consent should be. It seems
that whatever the circumstances, the information provided to
the patient must enable them to understand what is being done
and what are the benefits and inconveniencies of the proposed
treatment. This involves information on life expectancy (usually
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Table 1. Leading information
Protocol ID and title
Version no., date, page x/xx
You are being asked to take part in this trial because you have a cancer (describe the type and stage of the cancer such as ‘colon
cancer that has spread and has not responded to previous treatment’as well as the prognosis).
In order to allow you to make a free and informed decision to participate in this trial, good clinical research practices and regulations require that
you are fully informed about your disease, the available treatments and their possible benefits and risks. Your care provider will give you with all
information and alternatives for your next treatment options. It is strongly recommended that you read the document and ask questions to your
physician to clarify points that are not clear to you.
Background
Why is this trial
being done?
What are the characteristics
of the proposed treatment?
Duration of participation,
frequency of visits and
exams not done as
routine practice
What are my choices?
Are there benefits to taking
part in this trial?
What important adverse
reactions can I expect
being in the trial?
Your physician will explain to you the purpose of this clinical trial that includes an investigational treatment for your
disease. Clinical trials include only patients who freely choose to participate. You can only be chosen to join the
trial if you understand what will be done to you. Please discuss this with your doctor and your family and ask
about anything you are unclear of. Take as much time as you need to make your decision
Explain the purpose of clinical research and how it is carried out
The purpose of this trial is to evaluate the tolerability and the efficacy of a new anticancer treatment called Testdrug
against the standard treatment Standardrug. We are expecting that the new treatment may be more active (or better tolerated) than the current available ones, but we need to verify this hypothesis. If you agree to participate and
your disease condition will allow it, you will arbitrarily – like tossing a dice – be selected to receive either an investigational treatment or a treatment already approved for your health condition.
If appropriate: You may be selected to receive a placebo. A placebo is an inactive substance which has the same
presentation, and is administered, as the active treatment tested. The choice of a placebo is necessary in order to
properly evaluate the new treatment
The following treatment is planned in this clinical trial:
• The investigational drug: Give the drug name and whether it is a new investigational product, chemical or new
technology.
• Give information on the frequency and the route of administration (3x/week for 4 consecutive weeks repeated
every 6 weeks by oral/iv/im, etc)
• The commercially available medication will be provided as in routine medical practice.
• If you have completed the trial and did benefit from the new treatment, you may receive additional courses until
the drug is available on the market in your country. In case further investigations with that particular product are
abandoned for your disease, your treating physician will reevaluate your treatment options.
Before taking part in the trial, your physician will ask you to perform some exams and tests to find out whether you
can be in the trial. The majority of these exams and tests are part of routine medical care for your disease. Add
whether invasive procedures are planned (e.g. biopsies, bone marrow procedure, etc.)
The entire schedule of the planned visits and tests required during this trial are given in the appendix at the end of
this document.
You will receive either the investigational drug or the comparative treatment/placebo for up to XX weeks/months.
When your treatment is completed you will be followed up for up to xx weeks/months/years. The entire duration
of your participation can be up to XX months/years.
The total number of patients planned in this trial is XXX, to be enrolled by XX centers in XX countries.
Your choices may include:
• Participate in this clinical trial
• Getting treatment or care for your cancer without being in this trial
• Taking part in another trial
• Getting no treatment
• Getting comfort care, also called palliative care that helps reducing pain, tiredness, appetite problems and other
problems caused by your disease. It does not treat the cancer directly, but instead tries to improve how you feel.
Taking part in this trial may or may not make your health better. While doctors hope that this investigational treatment will be more useful against your disease compared with the known treatments, there is no proof of this yet.
We do know that the information collected in this trial will help doctors learn more about this new treatment and
this information may help future cancer patients.
If appropriate: In case you receive the placebo you will also receive the most active treatment available today for
your situation.
As with any drug, you may experience mild or more serious adverse reactions during the trial. You will be monitored
carefully for any of those reactions. However, doctors do not know all the adverse reactions that may occur. Many
adverse reactions go away soon after you stop your medication. In some cases, adverse reactions can become serious, long lasting, or may never go away they may require hospitalization and even, but rarely, lead to death.
Continued
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Table 1. Continued
Protocol ID and title
Version no., date, page x/xx
The known clinical important adverse reactions of the investigational drug are listed by frequency grouping (keep either EU or United States, as defined in the leading information above):
Information about standard treatment should also be given. For product(s) already on the market and used in this
trial, give summary of adverse reactions and refer to the information available in the package insert of that drug
(attached as an appendix). Patients should be informed that, outside of the present study trial, the same standard
treatments are likely to be administered with a similar level of adverse reactions.
This trial has been reviewed and approved by an independent Research Ethics Committee/Institutional Review
Board being responsible for assuring that your safety, rights, and welfare are protected.
The trial was also authorized by the health authorities in your country
Any additional research to this clinical trial:
You may be asked to have a biopsy (or surgery) to evaluate your disease. Your doctor will remove some body tissue
or perform analysis of blood samples to better define the nature of the tumor. The results of these analysis will be
given to you and will be used to plan your care.
We would like to keep some of the tissue that is left over for future research. If you agree, this tissue will be kept
and may be used in research to learn more about cancer and other diseases. The research that may be done with
your tissue is not designed specifically to help you. It might help people who have cancer and other diseases in
the future. The choice to let us keep the left over tissue for future research is up to you. No matter what you decide to do, it will not affect your care.
䊊 Yes, you can use the left over samples
䊊 No, I do not want you to use the samples, they must be destroyed
If yes, more information regarding this additional research is provided in the Relevant Supportive Information
document.
Ethics and approvals
OPTIONAL
Additional blood
and tissue research
I have read the information about this clinical trial. I understand that clinical trials include only patients who freely choose to participate. I had the
opportunity to ask questions and discuss them with my physician and my familly. All of my questions have been answered and I understand
enough about the trial information to judge that I want to participate in it.
I am aware that I can withdraw at any time. In the event of trial-related injury, I will receive treatment and that the sponsor will cover the cost.
I will be informed in a timely manner of any new relevant information that may change my decision to participate.x
The person of contact for further information is Dr. . .
I voluntarily give my consent to participate. My personal health information will not be disclosed and will be kept confidential, but I agree to
and authorize the use of my anonymous personal health data by the sponsor and health authorities for regulatory purposes.
I have been given a copy of xx pages of information.
Delete what is not applicable to the trial
I agree to take part in this clinical trial
䊊Yes
䊊No
Patient: (print name and signature)
Date
Investigator (print name and signature)
Date
I do agree to give blood/tissue samples for further research
䊊Yes
䊊No
Patient: (print name and signature)
Investigator (print name and signature)
Date
If yes,
Date
1. My blood/tissue samples may be kept for use in research to learn about, prevent, or treat cancer.
䊊Yes
䊊No
䊊not applicable
2. My blood/tissue samples may be kept for use in research to learn about, prevent or treat other diseases.
䊊Yes
䊊No
䊊not applicable
3. Someone may contact me in the future to ask me to take part in more research.
䊊Yes
䊊No
䊊not applicable
For the purposes of this document, guidelines and instructions within the leading information template are provided as italic text. If this document is
used to prepare your informed consent form, these should be deleted and specific information should be inserted.
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Table 2. Relevant supportive information
Protocol ID and title
Early termination or if
you want to leave
the trial
What’s happen to my
data in case I withdraw my consent
The treatment plan
Appointments and
exams to be carried out
Estimated blood
volumes
Risk of pregnancy
Compensation
reimbursement
Costs of treatment
Injury
Optional (delete if
not applicable)
blood/tissue for
additional research
Version no., date, page x/xx
Your participation in this trial may be ended without your consent for one of the following reasons:
• If your physician believes that it is in your best interest.
• If during the trial, your physician discovers that your disease has gotten worse.
• If you experience serious adverse reactions that your physician considers unacceptable.
• If you require treatment with drugs that are not allowed on this trial.
• If you refuse further treatment, or do not follow the schedule of assessments or do not return for follow-up as originally
planned.
• If the sponsor discontinues the drug development process.
• If there are provisions in case of early termination or for post-trial access to the treatment of patients who still need an
intervention identified as beneficial in the trial
If you withdraw your consent, this will prevent any further collection of data. However, your withdrawal does not affect the
data and material that have already been collected. Those data will be used in the framework of this research.
The treatment schedule planned in this clinical trial is:
• The new drug will be administered at the following schedule: . . ..
• The standard treatment will be given at the following schedule: . . ..
Your physician will review with you the schedule of the planned visits and tests that are required before, during and at the
end of the trial. The details are attached to this document as an appendix. It is your responsibility to attend the visits as
planned.
At each visit, XX ml of blood will be collected. At follow-up visit, XX ml of blood will be collected. Over the duration of your
participation in the trial, an estimated total amount of blood drawn for blood tests will be XX ml. The blood tests will be
drawn to evaluate your hematology, your blood chemistry, your kidney and liver function.
Serum pregnancy test for women of childbearing potential will be taken before starting the trial and repeated once every 3
months.
If you or a female partner of male patient become pregnant you should contact without delay the responsible person
(name and details) for your own (or this of your partner) safety and this of the child.
There is often not enough medical information to know about the effect of an investigational treatment on the unborn
child, this needs that patients sexually active (both woman and man and their partner) are required to use adequate
methods of birth control during the trial period.
If you are a woman of childbearing potential, you will have to make a pregnancy test to make certain you are not pregnant
before starting the trial.The test must be negative to participate in this trial.
You will not receive any financial compensation for participation in this trial. However, travel cost may be reimbursed by the
sponsor. If you wish to claim travel costs, discuss this with your physician before you decide to participate.
Neither you, nor your medical insurance provider will be expected to pay any costs directly related with this trial.
All routine procedures that would normally be given by your health care provider would continue to be covered by you
and/or your insurance provider.
The investigational drug must be provided to you free-of-charge.
Complications may arise during the course of therapy either due to your disease or due to the treatment you are receiving
for your disease. For any type of damages including injuries due to any substance or procedure properly given under the
plan for this trial, contact your physician (the sponsor is responsible to cover the treatment of any trial-related injury).
You agree to provide additional blood/tissue for researches that are not linked to this clinical trial.
About using tissue for research
Your tissue may be helpful for research whether you do or do not have cancer.
Unless otherwise requested, reports about research done with your tissue will not be given to you or your doctor. These reports will not be put in your health record. The research will not have an effect on your care.
Things to think about
If you decide now that your tissue can be kept for research, you can change your mind at any time. Just contact us and let
us know that you do not want us to use your tissue. Then any tissue that remains will no longer be used for research and
will be destroyed.
In the future, people who do research may need to know more about your health. While they may give them reports about
your health, it will not give them your name, address, phone number, or any other information that will let the researchers
know who you are.
Sometimes tissue is used for genetic research (about diseases that are passed on in families). Even if your tissue is used for
this kind of research, the results will not be put in your health records.
Your tissue will be used only for research and will not be sold. The research done with your tissue may help to develop
new treatment in the future.
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Table 2. Continued
Protocol ID and title
Contact information
Version no., date, page x/xx
Benefits
The benefits of research using tissue include learning more about what causes cancer and other diseases, how to prevent
them, and how to treat them.
Risks
The greatest risk to you is the release of information from your health records. We ensure that your personal information
will be kept private and confidential, according to the National law.
The physician in charge of this trial is Dr______________.
The telephone contact number is [telephone number]. If you need more information about this trial or if you have any
questions at any other time, you may contact your physician.
a few months for cancer patients), the potential survival benefit
(often weeks) and risks related to treatment. Some members of
ARCAD do not agree that the consent form is the best place to
discuss prognosis because they think that the uncertainty
around this information could be misleading to patients, but do
feel that the aims of care (curative, palliative, etc.) and goals of
treatment might help setting the scene of experimental intervention. They also agreed that if the patient cannot capture the essence of his situation, whatever the reasons, socio-cultural,
intellectual, emotional or communication problems, he should
not be part of a research program.
The informed consent documentation may be clearer if it is
structured in several sections but remains a single document with
the expected links between sections. The leading information
should highlight the key information on the disease and its treatment which are essential to make an informed decision (in agreement with the ICH-GCP E6 20 points, the 21 CFR 50.25
requirements and the NCI template), The additional detailed information part of the informed consent document, should provide the details on the schedule of events during the trial as well as
patient’s rights and protection, the coverage in case of trialrelated damages, data privacy, or the treatment option once the
trial is completed, or other trial-related specific requirement. It
could also contain additional information required by local
authorities, REC or IRBs. A third section would concern, if indicated, research associated with the study and should contain only
the details related to this research. Eventually annexes could contain more general information as a glossary. We think that the details on the disease status, the prognosis as well as the expected
benefit of the treatment must be as explicit as possible. The reality, even if it is tough to hear, must be in the framework of an experimental treatment. Patients with cancer and especially with
metastatic cancer must feel confident that the treatment option is
in-line with their expectation. The hope for a cancer cure may
push the patient to accept treatment he would refuse if he had
realized that the potential benefits would be modest. According
to some of the ARCAD Group members, this information does
not need to appear in a document of general information but it is
the duty of every physician to address these issues through a personalized relationship that is respectful of all persuasions.
Therefore, it is of paramount importance that patients understand that patients’ rights and regulations on patient protection
928 | Bleiberg et al.
require that they are fully informed about their disease, available
treatments and their possible benefit and risks. Patients must
have the opportunity to ask as many questions as necessary for
their understanding of the research and the formation of their
opinion.
Although any clinical trial is currently based on the
Declaration of Helsinki [2] and carried out according to the
international quality standards defined in ICH-GCP E6 guidelines [3], some approaches and practices remain countrydependent. As pointed out by the Declaration of Helsinki and regardless the country in which you practice, patients enrolled in
clinical trials must be able to fully understand the information
provided on the experimental nature of the treatment, its benefits
and risks. If this is not the case, they should not be recruited into
any research activities.
An essential aspect of the communication is the ease of reading
and the understanding of the text presented. Patients who receive
the information could have more than one reason (psychological
or physical) of not being able to read or understand the information: obsessed by cancer, emotional instability, attention disorders, low level of reading, eye disorders. Therefore, a special
effort has to be made to make it clear, unambiguous and easy to
read. This may require the help of a trained staff. In short recommendations are to keep the document within the boundaries previously defined, 1200–18 000 words for the leading part, 2000–
3000 for the detailed one, to plan what needs to be written, to cut
out any unnecessary detail, to present important ideas in a logical
order and, eventually, to use simple, clear text with short sentences, simple punctuation and no jargon, acronyms or abbreviations [19].
Simplifying informed consent documentation alone does not
always significantly improve participants’ comprehension. There
are still about 40% of the patients who do not understand a simplified information consent document [20]. They are many reasons causing such*** situation, including poor literacy skills,
poor health knowledge and probably fear to ask for clarification
of information even if they do not understand what the physician
has said. Doing nothing cannot be a solution. Our only choice is
to work on documents which can be understood by a larger number of patients. This being done, other approaches will be necessary to evaluate the process and, eventually, develop other
communication strategies.
Volume 28 | Issue 5 | 2017
Special article
Annals of Oncology
How patients participating in a clinical trial are informed
and respected as a person is a key factor in clinical research. It
reflects the interest that the sponsor, the investigators and the
medical community owes to patients. It is a guarantee of the
quality of the trial and the reinforced intrinsic value of the
data.
Funding
This article was done within the framework of the Fondation
A.R.CA.D activities. The authors received no financial support
from the Fondation A.R.CA.D. No grant number is applicable.
Disclosure
Acknowledgements
Magdalena Benetkiewicz (PhD) assisted the authors with reviewing/editing the manuscript before submission, her work
was funded by the Fondation A.R.CA.D.
Acknowledged for their contribution and support:
USA: C. Allegra (University of Florida Health Cancer Center,
Florida), J. Berlin (Vanderbilt-Ingram Cancer Center,
Nashville), B. Giantonio (The Perelman School of Medicine of
the University, Pennsylvania), R. Goldberg (The James Cancer
Hospital and Solove Research Institute, Columbus), A. Grothey
(Mayo Clinic, Rochester), S. Hamilton (M.D. Anderson Cancer
Center, Houston), H. Hurwitz (Duke University Cancer
Institute, Durham), S. Kopetz (M.D. Anderson Cancer Center,
Houston), H.J. Lenz (USC Norris Comprehensive Cancer
Center, Los Angeles), C. Lieu (University of Colorado Auschutz
Medical Campus, Denver), N. Meropol (University Hospital
Case Medical Center, Cleveland), L. Saltz (Memorial SloanKettering Cancer Center, New York), D. Sargent (Mayo Clinic,
Rochester), M. Tempero (Comprehensive Cancer Center
University of California, San Francisco).
Belgium: M. Buyse (IDDI, Louvain-la-Neuve), M. Peeters
(Antwerp University Hospital, Edegem), S. Tejpar (Universitair
Ziekenhuis Gasthuisberg Campus, Leuven), E. Van Cutsem
(Universitair Ziekenhuis Gasthuisberg Campus, Leuven).
Germany: D. Arnold (Klinik für Tumorbiologie, Freiburg), R.
Porschen (Klinikum Bremen-Ost, Bremen), V. Heinemann
(Klinikum der Universit€at München).
United Kingdom: R. Adams (Cardiff University and Velindre
Cancer Centre, Cardiff), R. Kaplan (University College
London), T.S Maughan (CRUK/MRC Oxford Institute for
Radiation Oncology, Oxford), M.T. Seymour (Cancer
Medicine & Consultant Medical Oncologist, University of
Leeds).
France: T. André (Hôpital Saint-Antoine, Paris), F. Bonnetain
(CHRU, Besançon), C. Louvet (Institut Mutualiste Montsouris,
Paris).
Spain: E. Diaz-Rubio (Hospital Clınico Universitario San
Carlos, Madrid), J. Tabernero (Vall d’Hebron Institute of
Oncology, Barcelona).
The Netherlands: C.J.A. Punt (Academisch Medisch Centrum,
University of Amsterdam), M. Koopman (Academisch Medisch
Centrum, University of Amsterdam).
Greece: I. Souglakos (University Hospital Heraklion, Crete).
Hungary: G. Bodoky (St. Laszl
o Hospital, Budapest).
Italy: A. Falcone (University Hospital S. Chiara, Istituto
Toscano Tumori, Pisa).
Israel: E. Shacham Shmueli (Sheba Medical Center Tel
Hashomer, Tel Aviv University).
International patients association: EuropaColon.
Volume 28 | Issue 5 | 2017
The authors have declared no conflicts of interest.
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Appendix
Table A1. Appendix to Table 2: Sample of schedule of events (protocol number)
Protocol ID and title
Visit day
One week before
starting
Version no., date, page x/xx
Exams, tests and other procedures
• A complete review of your medical history will be done prior treatments, as well as the medications you have taken the
last 4–6 weeks
• You will be asked about your ability to perform your daily activities
• Your physical examination will include your weight, height, blood pressure and pulse rate.
• You will have a blood test to check (approximately xx ml) your hematology, your blood chemistry, your kidney and liver
function to ensure that you can safely receive the trial medication
• You will have an electrocardiogram to measure your heart rhythm (if necessary)
• You may have a radiography or other imaging systems to evaluate your disease status.
• if you are a female of childbearing potential, a pregnancy test (B-HCG) will be carried out
• You may have a lung function test to know how your lungs work
Cycle 1Day 1
• . . .. . ..
• You will be ask about your ability to perform your daily activities
• A review of your signs and symptoms and your current medication will be done
• The physical examination will include your weight, blood pressure and pulse rate.
• Blood tests (approximately xx ml) will be drawn to evaluate your hematology, your blood chemistry, your kidney and liver
function to ensure that you can safely receive the next treatment
• You should provide information about the occurrence of any adverse event
• The drug XXXX will be given through your veins over xx hours
Cycle 1Day 8
• A review of your signs and symptoms and your current medication will be done
• Blood tests (approximately xx ml) will be drawn to evaluate your hematology, your blood chemistry, your kidney and liver
function to ensure that you can safely receive your next treatment
• You should provide information about the occurrence of any adverse event
• The drug XXXX will be given through your veins over xx hours
930 | Bleiberg et al.
Volume 28 | Issue 5 | 2017